Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4

ABSTRACT

The present invention relates to dual GLP-1/glucagon receptor agonists or optionally trigonal GLP-1/glucagon/GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

RELATED APPLICATIONS

This application is a 35 U.S.C. §111(a) filing claiming priority under35 U.S.C. §119(a)-(d) to European Patent Application No.EP2014/14305503.6, filed Apr. 7, 2014, the content of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to exendin-4 peptide analogues whichactivate the glucagon-like peptide 1 (GLP-1) and the glucagon (GCG)receptor and optionally the glucose-dependent insulinotropic polypeptide(GIP) receptor and their medical use, for example in the treatment ofdisorders of the metabolic syndrome, including diabetes and obesity, aswell as reduction of excess food intake.

BACKGROUND OF THE INVENTION

Exendin-4 is a 39 amino acid peptide which is produced by the salivaryglands of the Gila monster (Heloderma suspectum) (Eng J. et al., J.Biol. Chem., 1992, 267, 7402-05). Exendin-4 is an activator of theglucagon-like peptide-1 (GLP-1) receptor, whereas it shows only very lowactivation of the GIP receptor and does not activate the glucagonreceptor (see Table 1).

TABLE 1 Potencies of exendin-4 at human GLP-1, GIP and Glucagonreceptors (indicated in pM) at increasing concentrations and measuringthe formed cAMP as described in Methods. SEQ ID EC50 hGLP-1 R EC50 hGIPR EC50 hGlucagon R NO: peptide [pM] [pM] [pM] 1 exendin-4 0.4 12500.0>10000000

Exendin-4 shares many of the glucoregulatory actions observed withGLP-1. Clinical and non-clinical studies have shown that exendin-4 hasseveral beneficial antidiabetic properties including a glucose dependentenhancement in insulin synthesis and secretion, glucose dependentsuppression of glucagon secretion, slowing down gastric emptying,reduction of food intake and body weight, and an increase in beta-cellmass and markers of beta cell function (Gentilella R et al., DiabetesObes Metab., 11:544-56, 2009; Norris S L et al., Diabet Med., 26:837-46,2009; Bunck M C et al., Diabetes Care., 34:2041-7, 2011).

These effects are beneficial not only for diabetics but also forpatients suffering from obesity. Patients with obesity have a higherrisk of getting diabetes, hypertension, hyperlipidemia, cardiovascularand musculoskeletal diseases.

Relative to GLP-1 and GIP, exendin-4 is more resistant to cleavage bydipeptidyl peptidase-4 (DPP4) resulting in a longer half-life andduration of action in vivo (Eng J., Diabetes, 45 (Suppl 2):152A(abstract 554), 1996; Deacon C F, Horm Metab Res, 36: 761-5, 2004).

Exendin-4 was also shown to be much more stable towards degradation byneutral endopeptidase (NEP), when compared to GLP-1, glucagon oroxyntomodulin (Druce M R et al., Endocrinology, 150(4), 1712-1721,2009).

Nevertheless, exendin-4 is chemically labile due to methionine oxdiationin position 14 (Hargrove D M et al., Regul. Pept., 141: 113-9, 2007) aswell as deamidation and isomerization of asparagine in position 28 (WO2004/035623).

The amino acid sequence of exendin-4 is shown as SEQ ID NO: 1:

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH₂

The amino acid sequence of GLP-1(7-36)-amide is shown as SEQ ID NO: 2:

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂

Liraglutide is a marketed chemically modified GLP-1 analogue in which,among other modifications, a fatty acid is linked to a lysine inposition 20 leading to a prolonged duration of action (Drucker D J etal, Nature Drug Disc. Rev. 9, 267-268, 2010; Buse, J B et al., Lancet,374:39-47, 2009).

The amino acid sequence of Liraglutide is shown as SEQ ID NO: 3:

HAEGTFTSDVSSYLEGQAAK((S)-4-Carboxy-4-hexadecanoylamino-butyryl-)EFIAWLVRGRG-OH

Glucagon is a 29-amino acid peptide which is released into thebloodstream when circulating glucose is low. Glucagon's amino acidsequence is shown as SEQ ID NO: 5:

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH

During hypoglycemia, when blood glucose levels drop below normal,glucagon signals the liver to break down glycogen and release glucose,causing an increase of blood glucose levels to reach a normal level.Recent publications suggest that glucagon has in addition beneficialeffects on reduction of body fat mass, reduction of food intake, andincrease of energy expenditure (K M Heppner, Physiology & Behavior 2010,100, 545-548).

GIP (glucose-dependent insulinotropic polypeptide) is a 42 amino acidpeptide that is released from intestinal K-cells following food intake.GIP and GLP-1 are the two gut enteroendocrine cell-derived hormonesaccounting for the incretin effect, which accounts for over 70% of theinsulin response to an oral glucose challenge (Baggio L L, Drucker D J.Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131-2157).

GIP's amino acid sequence is shown as SEQ ID NO: 4:

YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH

Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol.2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1,liraglutide and exendin-4, improve glycemic control in patients withT2DM by reducing fasting and postprandial glucose (FPG and PPG).Peptides which bind and activate the GLP-1 receptor are described inpatent applications WO 98/08871 A1, WO2008/081418 A1 and WO2008/023050A1, the contents of which are herein incorporated by reference.

Designing hybrid molecules which combine agonism on the GLP-1 receptor,the glucagon receptor and optionally the GIP receptor offers thetherapeutic potential to achieve better reduction of blood glucoselevels, increased insulin secretion and an even more pronouncedsignificant effect on body weight reduction compared to the marketedGLP-1 agonist Liraglutide (Hjort et al. Journal of Biological Chemistry,269, 30121-30124, 1994; Day J W et al, Nature Chem Biol, 5: 749-757,2009).

Peptides which bind and activate both the GLP-1 and the glucagonreceptor and optionally the GIP receptor, and improve glycaemic control,suppress body weight gain and reduce food intake are described in patentapplications WO 2008/071972, WO 2008/101017, WO 2009/155258, WO2010/096052, WO 2010/096142, WO 2011/075393, WO 2008/152403, WO2010/070251, WO 2010/070252, WO 2010/070253, WO 2010/070255, WO2011/160630, WO 2011/006497, WO 2011/087671, WO 2011/087672,WO2011/117415, WO2011/117416, WO 2012/177443 WO 2012/177444, WO2012/150503, WO 2013/004983, WO 2013/092703, WO 2014/041195 and WO2014/041375, the contents of which are herein incorporated by reference.These applications disclose that mixed agonists of the GLP-1 receptor,the glucagon receptor and optionally the GIP receptor can be designed asanalogues of the native GLP-1 or glucagon sequences.

Bloom et al. (WO 2006/134340) disclose that peptides which bind andactivate both the glucagon and the GLP-1 receptor can be constructed ashybrid molecules from glucagon and exendin-4, where the N-terminal part(e.g. residues 1-14 or 1-24) originates from glucagon and the C-terminalpart (e.g. residues 15-39 or 25-39) originates from exendin-4. Suchpeptides comprise glucagon's amino acid motif YSKY in position 10-13.Krstenansky et al (Biochemistry, 25, 3833-3839, 1986) show theimportance of these residues 10-13 of glucagon for its receptorinteractions and activation of adenylate cyclase.

In the exendin-4 derivatives described in this invention, several of theunderlying residues are different from glucagon and the peptidesdescribed in WO 2006/134340. In particular residues Tyr10 and Tyr13,which are known to contribute to the fibrillation of glucagon (D EOtzen, Biochemistry, 45, 14503-14512, 2006) are replaced by Leu inposition 10 and Gln, a non-aromatic polar amino acid, in position 13.This replacement, especially in combination with isoleucine in position23 and glutamate in position 24, leads to exendin-4 derivatives withpotentially improved biophysical properties as solubility or aggregationbehaviour in solution. The non-conservative replacement of an aromaticamino acid with a polar amino acid in position 13 of an exendin-4analogue surprisingly leads to peptides with high activity on theglucagon receptor, keeping their activity on the GLP-1 receptor (seealso WO2013/186240.

Compounds of this invention are exendin-4 derivatives, which not onlyshow agonistic activity at the GLP-1 receptor but also at the glucagonreceptor and optionally the GIP receptor and which have only 4 or 5amino acid exchanges compared to native exendin-4 including—amongstothers—in position 14 an amino acid substituted with a lipophilicside-chain (e.g. a fatty acid combined with a linker).

Surprisingly, it was found that the modification of the amino acids inposition 2 and 3 of native exendin-4 in combination with a fatty acidacylated residue in position 14 leads to peptides with a significantlyhigher glucagon receptor activity than the corresponding peptides withotherwise identical amino acid sequence with methionine (as inexendin-4) or leucine in position 14 (see Table 7). Additionally, thisfatty acid functionalization in position 14 results in an improvedpharmacokinetic profile.

Compounds of this invention are more resistant to cleavage by neutralendopeptidase (NEP) and dipeptidyl peptidase-4 (DPP4), resulting in alonger half-life and duration of action in vivo, when compared withnative GLP-1 and glucagon.

Compounds of this invention preferably are soluble not only at neutralpH, but also at pH 4.5. This property potentially allows co-formulationfor a combination therapy with an insulin or insulin derivative andpreferably with a basal insulin like insulin glargine/Lantus®.

BRIEF SUMMARY OF THE INVENTION

Provided herein are exendin-4 analogues with only 4 or 5 amino acidmodifications (compared to native exendin-4) which potently activate notonly the GLP-1 receptor but also the glucagon receptor and optionallythe GIP receptor. In these exendin-4 analogues—among othersubstitutions—methionine at position 14 is replaced by an amino acidcarrying an —NH₂ group in the side-chain, which is further substitutedwith a lipophilic side-chain (e.g. a fatty acid optionally combined witha linker).

The invention provides a peptidic compound having the formula (I):

(I) H₂N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-R¹

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents an amino acid residue with a functionalized —NH₂        side chain group, selected from the group consisting of Lys,        Orn, Dab, or Dap, wherein the —NH₂ side chain group is        functionalized by —Z—C(O)—R⁵, wherein        -   Z represents a linker in all stereoisomeric forms and        -   R⁵ is a moiety comprising up to 50 carbon atoms and            heteroatoms selected from N and O,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ is NH₂ or OH,        -   or a salt or solvate thereof.

The compounds of the invention are GLP-1 and glucagon receptor agonistsand optionally GIP receptor agonists as determined by the observationthat they are capable of stimulating intracellular cAMP formation in theassay system described in Methods.

In addition, the peptidic compound, particularly with a lysine atposition 14 which is further substituted with a lipophilic residue,exhibits a relative activity of at least 0.1% (i.e. EC₅₀<700 pM),preferably at least 1% (i.e. EC₅₀<70 pM) and more preferably at least 5%(i.e. EC₅₀<14 pM) compared to that of GLP-1(7-36)-amide at the GLP-1receptor.

In addition, the peptidic compound, particularly with a lysine atposition 14 which is further substituted with a lipophilic residue,exhibits a relative activity of at least 0.1% (i.e. EC₅₀<1000 pM), morepreferably 0.3% (i.e. EC₅₀<333 pM) and even more preferably 1% (i.e.EC₅₀<100 pM) compared to that of natural glucagon at the glucagonreceptor.

Optionally, in some embodiments, the peptidic compound, particularlywith a lysine at position 14 which is further substituted with alipophilic residue, exhibits a relative activity of at least 0.01% (i.e.EC₅₀<4000 pM), preferably at least 0.02% (i.e. EC₅₀<2000 pM), morepreferably at least 0.04% (i.e. EC₅₀<1000 pM), more preferably at least0.1% (i.e. EC₅₀<400 pM), and even more preferably at least 0.2% (i.e.EC₅₀<200 pM) compared to that of natural GIP at the GIP receptor.

The term “activity” as used herein preferably refers to the capabilityof a compound to activate the human GLP-1 receptor, the human glucagonreceptor and optionally the human GIP receptor. More preferably the term“activity” as used herein refers to the capability of a compound tostimulate intracellular cAMP formation. The term “relative activity” asused herein is understood to refer to the capability of a compound toactivate a receptor in a certain ratio as compared to another receptoragonist or as compared to another receptor. The activation of thereceptors by the agonists (e.g. by measuring the cAMP level) isdetermined as described herein, e.g. as described in Example 4.

According to one embodiment, the compounds of the invention have an EC₅₀for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less,more preferably of 100 pM or less, more preferably of 75 pM or less,more preferably of 50 pM or less, more preferably of 40 pM or less, morepreferably of 30 pM or less, and more preferably of 20 pM or less.

According to one embodiment, the compounds of the invention have an EC₅₀for hGlucagon receptor of 500 pM or less, more preferably of 300 pM orless, more preferably of 200 pM or less, more preferably of 150 pM orless, more preferably of 100 pM or less.

According to another embodiment, the compounds of the invention haveoptionally an EC₅₀ for hGIP receptor of 2000 pM or less, preferably of500 pM or less, more preferably of 200 pM or less, more preferably of150 pM or less, more preferably of 100 pM or less.

According to another embodiment, the compounds of the invention have anEC₅₀ for hGLP-1 receptor of 500 pM or less, preferably of 200 pM orless, more preferably of 150 pM or less, more preferably of 100 pM orless, more preferably of 90 pM or less, more preferably of 80 pM orless, more preferably of 70 pM or less, more preferably of 60 pM orless, more preferably of 50 pM or less, more preferably of 40 pM orless, more preferably of 30 pM or less, and more preferably of 20 pM orless, and/or an EC₅₀ for hGlucagon receptor of 500 pM or less,preferably of 400 pM or less, more preferably of 350 pM or less, morepreferably of 200 pM or less, more preferably of 150 pM or less, morepreferably of 100 pM or less, and/or optionally an EC₅₀ for hGIPreceptor of 2000 pM or less, preferably of 500 pM or less, morepreferably of 200 pM or less, more preferably of 150 pM or less, morepreferably of 100 pM or less.

In still another embodiment, the EC₅₀ for both receptors, i.e. for thehGLP-1 receptor and for the hGlucagon receptor, is 500 pM or less, morepreferably 200 pM or less, more preferably 100 pM or less, morepreferably 75 pM or less, more preferably 50 pM or less, more preferably25 pM or less.

In still another embodiment, the EC₅₀ for all three receptors, i.e. forthe hGLP-1 receptor, for the hGlucagon receptor and for the hGIPreceptor, is 500 pM or less, more preferably 200 pM or less, morepreferably 100 pM or less, more preferably 75 pM or less, morepreferably 50 pM or less, more preferably 25 pM or less.

The EC₅₀ for hGLP-1 receptor, hGlucagon receptor and hGIP receptor maybe determined as described in the Methods herein and as used to generatethe results described in Example 4.

The compounds of the invention have the ability to reduce the intestinalpassage, to increase the gastric content and/or to reduce the foodintake of a patient. These activities of the compounds of the inventioncan be assessed in animal models known to the skilled person and alsodescribed herein in the Methods.

The compounds of the invention have the ability to reduce blood glucoselevel, and/or to reduce HbA1c levels of a patient. These activities ofthe compounds of the invention can be assessed in animal models known tothe skilled person and also described herein in the Methods.

The compounds of the invention also have the ability to reduce bodyweight of a patient. These activities of the compounds of the inventioncan be assessed in animal models known to the skilled person and alsodescribed herein in the Methods.

Surprisingly, it was found that peptidic compounds of the formula (I),particularly those with a lysine (or close analogues) at position 14which is further substituted with a lipophilic residue, showed verypotent GLP-1 receptor and glucagon receptor and optionally GIP receptoractivation.

It is described in the literature (Murage E N et al., Bioorg. Med. Chem.16 (2008), 10106-10112), that a GLP-1 analogue with an acetylated lysineat position 14 showed significantly reduced potency on the GLP-1receptor compared to natural GLP-1.

Furthermore, oxidation (in vitro or in vivo) of methionine, present inthe core structure of exendin-4, is not possible anymore for peptidiccompounds of the formula (I).

Further, compounds of the invention preferably have a high solubility atacidic and/or physiological pH values, e.g. at pH 4.5 and/or at pH 7.4at 25° C., in another embodiment at least 0.5 mg/ml and in a particularembodiment at least 1.0 mg/ml.

Furthermore, according to one embodiment, compounds of the inventionpreferably have a high stability when stored in solution. Preferredassay conditions for determining the stability is storage for 7 days at40° C. in solution at pH 4.5 or pH 7.4. The remaining amount of peptideis determined by chromatographic analyses as described in Methods andExamples. Preferably, after 7 days at 40° C. in solution at pH 4.5 or pH7.4, the remaining peptide is at least 80%, more preferably at least85%, even more preferably at least 90% and even more preferably at least95%.

Preferably, the compounds of the present invention comprise a peptidemoiety which is a linear sequence of 39 amino carboxylic acids,particularly α-amino carboxylic acids linked by peptide, i.e.carboxamide, bonds.

In a further embodiment, R¹ is NH₂ and in a further embodiment R¹ is OH.

Specific preferred examples for —Z—C(O)—R⁵ groups are listed in thefollowing Table 2, which are selected from(S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,[2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl.

Further preferred are stereoisomers, particularly enantiomers of thesegroups, either S- or R-enantiomers. The term “R” in Table 2 is intendedto mean the attachment site of —Z—C(O)—R⁵ at the peptide back bone, i.e.particularly the r-amino group of Lys.

TABLE 2 Structure/IUPAC name

E-x70

E-x53

E- E-x53

AEEAc- AEEAc- E-x53

AEEAc- AEEAc- E-x70

AEEAc- AEEAc- AEEAc- x70

AEEAc- AEEAc- E-x99

A further embodiment relates to a group of compounds, wherein

X14 represents Lys wherein the —NH₂ side chain group is functionalizedwith a group —Z—C(O)R⁵, wherein

Z represents a group selected from γE, γE-γE, AEEAc-AEEAc-γE andAEEAc-AEEAc-AEEAc and

R⁵ represents a group selected from pentadecanyl, heptadecanyl or16-carboxy-hexadecanyl.

A further embodiment relates to a group of compounds, wherein

X14 represents Lys wherein the —NH₂ side chain group is functionalizedwith a group —Z—C(O)R⁵, wherein

Z represents a group selected from γE, γE-γE, AEEAc-AEEAc-γE andAEEAc-AEEAc-AEEAc and

R⁵ represents a group selected from pentadecanyl or heptadecanyl.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents Ser,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,    -   X15 represents Glu,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents D-Ser,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents Gln,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from D-Ser and Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,    -   X15 represents Glu,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,    -   X15 represents Glu,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,    -   X15 represents Glu,    -   X28 represents an amino acid residue selected from Ala and Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from D-Ser and Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,    -   X15 represents Asp,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-(17-carboxy-heptadecanoyl)amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from Ser, D-Ser and        Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,        [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents an amino acid residue selected from D-Ser and Aib,    -   X3 represents an amino acid residue selected from Gln and His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,    -   X15 represents Glu,    -   X28 represents Lys,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X2 represents Aib,    -   X3 represents His,    -   X14 represents Lys wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X28 represents Ala,    -   R¹ represents NH₂,    -   or a salt or solvate thereof.

A further embodiment relates to a group of compounds, wherein

-   -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-    -   or a salt or solvate thereof.

A still further embodiment relates to a group of compounds, wherein

-   -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by        (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-.    -   or a salt or solvate thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 6-31 as well as salts and/or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 6-29 and 31 as well as salts and/or solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 8, 11 and 12 as well as salts and/or solvates thereof.

In certain embodiments, i.e. when the compound of formula (I) comprisesgenetically encoded amino acid residues, the invention further providesa nucleic acid (which may be DNA or RNA) encoding said compound, anexpression vector comprising such a nucleic acid, and a host cellcontaining such a nucleic acid or expression vector.

In a further aspect, the present invention provides a compositioncomprising a compound of the invention in admixture with a carrier. Inpreferred embodiments, the composition is a pharmaceutically acceptablecomposition and the carrier is a pharmaceutically acceptable carrier.The compound of the invention may be in the form of a salt, e.g. apharmaceutically acceptable salt or a solvate, e.g. a hydrate. In stilla further aspect, the present invention provides a composition for usein a method of medical treatment, particularly in human medicine.

In certain embodiments, the nucleic acid or the expression vector may beused as therapeutic agents, e.g. in gene therapy.

The compounds of formula (I) are suitable for therapeutic applicationwithout an additional therapeutically effective agent. In otherembodiments, however, the compounds are used together with at least oneadditional therapeutically active agent, as described in “combinationtherapy”.

The compounds of formula (I) are particularly suitable for the treatmentor prevention of diseases or disorders caused by, associated with and/oraccompanied by disturbances in carbohydrate and/or lipid metabolism,e.g. for the treatment or prevention of hyperglycemia, type 2 diabetes,impaired glucose tolerance, type 1 diabetes, obesity and metabolicsyndrome. Further, the compounds of the invention are particularlysuitable for the treatment or prevention of degenerative diseases,particularly neurodegenerative diseases.

The compounds described find use, inter alia, in preventing weight gainor promoting weight loss. By “preventing” is meant inhibiting orreducing when compared to the absence of treatment, and is notnecessarily meant to imply complete cessation of a disorder.

The compounds of the invention may cause a decrease in food intakeand/or increase in energy expenditure, resulting in the observed effecton body weight.

Independently of their effect on body weight, the compounds of theinvention may have a beneficial effect on circulating cholesterollevels, being capable of improving lipid levels, particularly LDL, aswell as HDL levels (e.g. increasing HDL/LDL ratio).

Thus, the compounds of the invention can be used for direct or indirecttherapy of any condition caused or characterised by excess body weight,such as the treatment and/or prevention of obesity, morbid obesity,obesity linked inflammation, obesity linked gallbladder disease, obesityinduced sleep apnea. They may also be used for treatment and preventionof the metabolic syndrome, diabetes, hypertension, atherogenicdyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease,or stroke. Their effects in these conditions may be as a result of orassociated with their effect on body weight, or may be independentthereof.

Preferred medical uses include delaying or preventing diseaseprogression in type 2 diabetes, treating metabolic syndrome, treatingobesity or preventing overweight, for decreasing food intake, increaseenergy expenditure, reducing body weight, delaying the progression fromimpaired glucose tolerance (IGT) to type 2 diabetes; delaying theprogression from type 2 diabetes to insulin-requiring diabetes;regulating appetite; inducing satiety; preventing weight regain aftersuccessful weight loss; treating a disease or state related tooverweight or obesity; treating bulimia; treating binge eating; treatingatherosclerosis, hypertension, type 2 diabetes, IGT, dyslipidemia,coronary heart disease, hepatic steatosis, treatment of beta-blockerpoisoning, use for inhibition of the motility of the gastrointestinaltract, useful in connection with investigations of the gastrointestinaltract using techniques such as X-ray, CT- and NMR-scanning.

Further preferred medical uses include treatment or prevention ofdegenerative disorders, particularly neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, Huntington's disease, ataxia,e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewybody dementia, multi-systemic atrophy, amyotrophic lateral sclerosis,primary lateral sclerosis, spinal muscular atrophy, prion-associateddiseases, e.g. Creutzfeldt-Jacob disease, multiple sclerosis,telangiectasia, Batten disease, corticobasal degeneration, subacutecombined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease,toxic encephalopathy, infantile Refsum disease, Refsum disease,neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Josephdisease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehogsyndrome, proteopathy, cerebral β-amyloid angiopathy, retinal ganglioncell degeneration in glaucoma, synucleinopathies, tauopathies,frontotemporal lobar degeneration (FTLD), dementia, cadasil syndrome,hereditary cerebral hemorrhage with amyloidosis, Alexander disease,seipinopathies, familial amyloidotic neuropathy, senile systemicamyloidosis, serpinopathies, AL (light chain) amyloidosis (primarysystemic amyloidosis), AH (heavy chain) amyloidosis, AA (secondary)amyloidosis, aortic medial amyloidosis, ApoAI amyloidosis, ApoAIIamyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnishtype (FAF), Lysozyme amyloidosis, Fibrinogen amyloidosis, Dialysisamyloidosis, Inclusion body myositis/myopathy, Cataracts, Retinitispigmentosa with rhodopsin mutations, medullary thyroid carcinoma,cardiac atrial amyloidosis, pituitary prolactinoma, Hereditary latticecorneal dystrophy, Cutaneous lichen amyloidosis, Mallory bodies, corneallactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic(Pindborg) tumor amyloid, cystic fibrosis, sickle cell disease orcritical illness myopathy (CIM).

Further medical uses include treatment of bone related disorders, suchas osteoporosis or osteoarthritis, etc., where increased bone formationand decreased bone resorption might be beneficial.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The amino acid sequences of the present invention contain theconventional one letter and three letter codes for naturally occurringamino acids, as well as generally accepted three letter codes for otheramino acids, such as Aib (α-aminoisobutyric acid), Orn (ornithin), Dab(2,4-diamino butyric acid) or Dap (2,3-diamino propionic acid).

The term “native exendin-4” refers to native exendin-4 having thesequence

(SEQ ID NO: 1) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH₂.

The invention provides peptidic compounds as defined above.

The peptidic compounds of the present invention comprise a linearbackbone of amino carboxylic acids linked by peptide, i.e. carboxamidebonds. Preferably, the amino carboxylic acids are α-amino carboxylicacids and more preferably L-α-amino carboxylic acids, unless indicatedotherwise. The peptidic compounds preferably comprise a backbonesequence of 39 amino carboxylic acids.

The peptidic compounds of the present invention may have unmodifiedside-chains, but carry at least one modification at one of the sidechains.

For the avoidance of doubt, in the definitions provided herein, it isgenerally intended that the sequence of the peptidic moiety (I) differsfrom native exendin-4 at least at one of those positions which arestated to allow variation. Amino acids within the peptide moiety (I) canbe considered to be numbered consecutively from 0 to 39 in theconventional N-terminal to C-terminal direction. Reference to a“position” within peptidic moiety (I) should be constructed accordingly,as should reference to positions within native exendin-4 and othermolecules, e.g., in exendin-4, His is at position 1, Gly at position 2,. . . , Met at position 14, . . . and Ser at position 39.

An amino acid residue with an —NH₂ side chain group, e.g. Lys, Orn, Dabor Dap, is functionalized in that at least one H atom of the —NH₂ sidechain group is replaced by —Z—C(O)—R⁵, wherein R⁵ comprises a lipophilicmoiety, e.g. an acyclic linear or branched (C₈-C₃₀) saturated orunsaturated hydrocarbon group, which is unsubstituted or substitutede.g. by halogen, —OH and/or CO₂H and Z comprises a linker in allstereoisomeric forms, e.g. a linker comprising one or more, e.g. 1 to 5,preferably 1, 2 or 3 amino acid linker groups selected from the groupγ-Glutamate (γE) and AEEAc. Preferred groups R⁵ comprise a lipophilicmoiety, e.g. an acyclic linear or branched (C₁₂-C₂₀) saturated orunsaturated hydrocarbon group, e.g. pentadecanyl, hexadecanyl orheptadecanyl, which is unsubstituted or substituted by CO₂H, morepreferably pentadecanyl, heptadecanyl or 16-carboxy-hexadecanyl. In oneembodiment amino acid linker groups are selected from γE, γE-γE,AEEAc-AEEAc-γE and AEEAc-AEEAc-AEEAc. In another embodiment the aminoacid linker group is γE. In another embodiment the amino acid linkergroup is γE-γE. In another embodiment the amino acid linker group isAEEAc-AEEAc-γE. In another embodiment the amino acid linker group isAEEAc-AEEAc-AEEAc.

In a further aspect, the present invention provides a compositioncomprising a compound of the invention as described herein, or a salt orsolvate thereof, in admixture with a carrier.

In a further aspect, the present invention provides a compositioncomprising a compound of the invention as described herein, or a salt orsolvate thereof, in admixture with a carrier.

The invention also provides the use of a compound of the presentinvention for use as a medicament, particularly for the treatment of acondition as described below.

The invention also provides a composition wherein the composition is apharmaceutically acceptable composition, and the carrier is apharmaceutically acceptable carrier.

Peptide Synthesis

The skilled person is aware of a variety of different methods to preparethe peptides that are described in this invention. These methods includebut are not limited to synthetic approaches and recombinant geneexpression. Thus, one way of preparing these peptides is the synthesisin solution or on a solid support and subsequent isolation andpurification. A different way of preparing the peptides is geneexpression in a host cell in which a DNA sequence encoding the peptidehas been introduced. Alternatively, the gene expression can be achievedwithout utilizing a cell system. The methods described above may also becombined in any way.

A preferred way to prepare the peptides of the present invention issolid phase synthesis on a suitable resin. Solid phase peptide synthesisis a well-established methodology (see for example: Stewart and Young,Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, Ill.,1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. APractical Approach, Oxford-IRL Press, New York, 1989). Solid phasesynthesis is initiated by attaching an N-terminally protected amino acidwith its carboxy terminus to an inert solid support carrying a cleavablelinker. This solid support can be any polymer that allows coupling ofthe initial amino acid, e.g. a trityl resin, a chlorotrityl resin, aWang resin or a Rink resin in which the linkage of the carboxy group (orcarboxamide for Rink resin) to the resin is sensitive to acid (when Fmocstrategy is used). The polymer support must be stable under theconditions used to deprotect the α-amino group during the peptidesynthesis.

After the first amino acid has been coupled to the solid support, theα-amino protecting group of this amino acid is removed. The remainingprotected amino acids are then coupled one after the other in the orderrepresented by the peptide sequence using appropriate amide couplingreagents, for example BOP, HBTU, HATU or DIC(N,N′-diisopropylcarbodiimide)/HOBt (1-hydroxybenzotriazole), whereinBOP, HBTU and HATU are used with tertiary amine bases. Alternatively,the liberated N-terminus can be functionalized with groups other thanamino acids, for example carboxylic acids, etc.

Usually, reactive side-chain groups of the amino acids are protectedwith suitable blocking groups. These protecting groups are removed afterthe desired peptides have been assembled. They are removed concomitantlywith the cleavage of the desired product from the resin under the sameconditions. Protecting groups and the procedures to introduce protectinggroups can be found in Protective Groups in Organic Synthesis, 3rd ed.,Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999).

In some cases it might be desirable to have side-chain protecting groupsthat can selectively be removed while other side-chain protecting groupsremain intact. In this case the liberated functionality can beselectively functionalized. For example, a lysine may be protected withan ivDde ([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl)protecting group (S. R. Chhabra et al., Tetrahedron Lett. 39, (1998),1603) which is labile to a very nucleophilic base, for example 4%hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal aminogroup and all side-chain functionalities are protected with acid labileprotecting groups, the ivDde group can be selectively removed using 4%hydrazine in DMF and the corresponding free amino group can then befurther modified, e.g. by acylation. The lysine can alternatively becoupled to a protected amino acid and the amino group of this amino acidcan then be deprotected resulting in another free amino group which canbe acylated or attached to further amino acids.

Finally the peptide is cleaved from the resin. This can be achieved byusing King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J.Peptide Protein Res. 36, 1990, 255-266). The raw material can then bepurified by chromatography, e.g. preparative RP-HPLC, if necessary.

Potency

As used herein, the term “potency” or “in vitro potency” is a measurefor the ability of a compound to activate the receptors for GLP-1,glucagon or GIP in a cell-based assay. Numerically, it is expressed asthe “EC50 value”, which is the effective concentration of a compoundthat induces a half maximal increase of response (e.g. formation ofintracellular cAMP) in a dose-response experiment.

Therapeutic Uses

Metabolic syndrome is a combination of medical disorders that, whenoccurring together, increase the risk of developing type 2 diabetes, aswell as atherosclerotic vascular disease, e.g. heart disease and stroke.Defining medical parameters for the metabolic syndrome include diabetesmellitus, impaired glucose tolerance, raised fasting glucose, insulinresistance, urinary albumin secretion, central obesity, hypertension,elevated triglycerides, elevated LDL cholesterol and reduced HDLcholesterol.

Obesity is a medical condition in which excess body fat has accumulatedto the extent that it may have an adverse effect on health and lifeexpectancy and due to its increasing prevalence in adults and childrenit has become one of the leading preventable causes of death in modernworld. It increases the likelihood of various other diseases, includingheart disease, type 2 diabetes, obstructive sleep apnea, certain typesof cancer, as well as osteoarthritis, and it is most commonly caused bya combination of excess food intake, reduced energy expenditure, as wellas genetic susceptibility.

Diabetes mellitus, often simply called diabetes, is a group of metabolicdiseases in which a person has high blood sugar levels, either becausethe body does not produce enough insulin, or because cells do notrespond to the insulin that is produced. The most common types ofdiabetes are: (1) type 1 diabetes, where the body fails to produceinsulin; (2) type 2 diabetes, where the body fails to use insulinproperly, combined with an increase in insulin deficiency over time, and(3) gestational diabetes, where women develop diabetes due to theirpregnancy. All forms of diabetes increase the risk of long-termcomplications, which typically develop after many years. Most of theselong-term complications are based on damage to blood vessels and can bedivided into the two categories “macrovascular” disease, arising fromatherosclerosis of larger blood vessels and “microvascular” disease,arising from damage of small blood vessels. Examples for macrovasculardisease conditions are ischemic heart disease, myocardial infarction,stroke and peripheral vascular disease. Examples for microvasculardiseases are diabetic retinopathy, diabetic nephropathy, as well asdiabetic neuropathy.

The receptors for GLP-1 and GIP as well as glucagon are members of thefamily of 7-transmembrane-spanning, heterotrimeric G-protein coupledreceptors. They are structurally related to each other and share notonly a significant level of sequence identity, but have also similarmechanisms of ligand recognition and intracellular signaling pathways.

Similarly, the peptides GLP-1, GIP and glucagon share regions of highsequence identity/similarity. GLP-1 and glucagon are produced from acommon precursor, preproglucagon, which is differentially processed in atissue-specific manner to yield e.g. GLP-1 in intestinal endocrine cellsand glucagon in alpha cells of pancreatic islets. GIP is derived from alarger proGIP prohormone precursor and is synthesized and released fromK-cells located in the small intestine.

The peptidic incretin hormones GLP-1 and GIP are secreted by intestinalendocrine cells in response to food and account for up to 70% ofmeal-stimulated insulin secretion. Evidence suggests that GLP-1secretion is reduced in subjects with impaired glucose tolerance or type2 diabetes, whereas responsiveness to GLP-1 is still preserved in thesepatients. Thus, targeting of the GLP-1 receptor with suitable agonistsoffers an attractive approach for treatment of metabolic disorders,including diabetes. The receptor for GLP-1 is distributed widely, beingfound mainly in pancreatic islets, brain, heart, kidney and thegastrointestinal tract. In the pancreas, GLP-1 acts in a strictlyglucose-dependent manner by increasing secretion of insulin from betacells. This glucose-dependency shows that activation of GLP-1 receptorsis unlikely to cause hypoglycemia. Also the receptor for GIP is broadlyexpressed in peripheral tissues including pancreatic islets, adiposetissue, stomach, small intestine, heart, bone, lung, kidney, testis,adrenal cortex, pituitary, endothelial cells, trachea, spleen, thymus,thyroid and brain. Consistent with its biological function as incretinhormone, the pancreatic β-cell express the highest levels of thereceptor for GIP in humans. There is some clinical evidence that theGIP-receptor mediated signaling could be impaired in patients with T2DMbut GIP-action is shown to be reversible and can be restored withimprovement of the diabetic status. Of note, the stimulation of insulinsecretion by both incretin hormones, GIP and GLP-1 is strictlyglucosed-dependent ensuring a mechanism associated with a low risk forhypoglycemia.

At the beta cell level, GLP-1 and GIP have been shown to promote glucosesensitivity, neogenesis, proliferation, transcription of proinsulin andhypertrophy, as well as antiapoptosis. A peptide with dual agonisticactivity for the GLP-1 and the GIP receptor could be anticipated to haveadditive or synergistic anti-diabetic benefit. Other relevant effects ofGLP-1 beyond the pancreas include delayed gastric emptying, increasedsatiety, decreased food intake, reduction of body weight, as well asneuroprotective and cardioprotective effects. In patients with type 2diabetes, such extrapancreatic effects could be particularly importantconsidering the high rates of comorbidities like obesity andcardiovascular disease. Further GIP actions in peripheral tissues beyondthe pancreas comprise increased bone formation and decreased boneresorption as well as neuroprotective effects which might be beneficialfor the treatment of osteoporosis and cognitive defects like Alzheimer'sdisease. Glucagon is a 29 amino acid peptide hormone that is produced bypancreatic alpha cells and released into the bloodstream whencirculating glucose is low. An important physiological role of glucagonis to stimulate glucose output in the liver, which is a processproviding the major counterregulatory mechanism for insulin inmaintaining glucose homeostasis in vivo.

Glucagon receptors are however also expressed in extrahepatic tissuessuch as kidney, heart, adipocytes, lymphoblasts, brain, retina, adrenalgland and gastrointestinal tract, suggesting a broader physiologicalrole beyond glucose homeostasis. Accordingly, recent studies havereported that glucagon has therapeutically positive effects on energymanagement, including stimulation of energy expenditure andthermogenesis, accompanied by reduction of food intake and body weightloss. Altogether, stimulation of glucagon receptors might be useful inthe treatment of obesity and the metabolic syndrome.

Oxyntomodulin is a peptide hormone consisting of glucagon with an eightamino acids encompassing C-terminal extension. Like GLP-1 and glucagon,it is pre-formed in preproglucagon and cleaved and secreted in atissue-specific manner by endocrinal cells of the small bowel.Oxyntomodulin is known to stimulate both the receptors for GLP-1 andglucagon and is therefore the prototype of a dual agonist.

As GLP-1 and GIP are known for their anti-diabetic effects, GLP-1 andglucagon are both known for their food intake-suppressing effects andglucagon is also a mediator of additional energy expenditure, it isconceivable that a combination of the activities of the two or threehormones in one molecule can yield a powerful medication for treatmentof the metabolic syndrome and in particular its components diabetes andobesity.

Accordingly, the compounds of the invention may be used for treatment ofglucose intolerance, insulin resistance, pre-diabetes, increased fastingglucose (hyperglycemia), type 2 diabetes, hypertension, dyslipidemia,arteriosclerosis, coronary heart disease, peripheral artery disease,stroke or any combination of these individual disease components.

In addition, they may be used for control of appetite, feeding andcalorie intake, increase of energy expenditure, prevention of weightgain, promotion of weight loss, reduction of excess body weight andaltogether treatment of obesity, including morbid obesity.

The compounds of the invention are agonists for the receptors for theGLP-1 and for the glucagon as well as optionally the GIP receptor (e.g.“dual or trigonal agonists”). Such peptides that are GLP-1/glucagonreceptor co-agonists, or GLP-1/glucagon/GIP receptor co-agonists mayprovide therapeutic benefit to address a clinical need for targeting themetabolic syndrome by allowing simultaneous treatment of diabetes andobesity.

Further disease states and health conditions which could be treated withthe compounds of the invention are obesity-linked inflammation,obesity-linked gallbladder disease and obesity-induced sleep apnea.

In one embodiment the compounds are useful in the treatment orprevention of hyperglycemia, type 2 diabetes, obesity.

Although all these conditions could be associated directly or indirectlywith obesity, the effects of the compounds of the invention may bemediated in whole or in part via an effect on body weight, orindependent thereof.

Further, diseases to be treated are neurodegenerative diseases such asAlzheimer's disease or Parkinson's disease, or other degenerativediseases as described above.

Compared to GLP-1, glucagon and oxyntomodulin, exendin-4 has beneficialphysicochemical properties, such as solubility and stability in solutionand under physiological conditions (including enzymatic stabilitytowards degradation by enzymes, such as DPP4 or NEP), which results in alonger duration of action in vivo. Therefore, exendin-4 might serve asgood starting scaffold to obtain exendin-4 analogues with dual or eventriple pharmacologies, e.g., GLP-1/glucagon and optionally in additionGIP receptor agonism.

Nevertheless, also exendin-4 has been shown to be chemically labile dueto methionine oxdiation in position 14 as well as deamidation andisomerization of asparagine in position 28. Therefore, stability mightbe further improved by substitution of methionine at position 14 and theavoidance of sequences that are known to be prone to degradation viaaspartimide formation, especially Asp-Gly or Asn-Gly at positions 28 and29.

Pharmaceutical Compositions

The term “pharmaceutical composition” indicates a mixture containingingredients that are compatible when mixed and which may beadministered. A pharmaceutical composition may include one or moremedicinal drugs. Additionally, the pharmaceutical composition mayinclude carriers, buffers, acidifying agents, alkalizing agents,solvents, adjuvants, tonicity adjusters, emollients, expanders,preservatives, physical and chemical stabilizers e.g. surfactants,antioxidants and other components, whether these are considered activeor inactive ingredients. Guidance for the skilled in preparingpharmaceutical compositions may be found, for example, in Remington: TheScience and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R.,2000, Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed),Handbook of Pharmaceutical Excipients, PhP, May 2013 update.

The exendin-4 peptide derivatives of the present invention, or saltsthereof, are administered in conjunction with an acceptablepharmaceutical carrier, diluent, or excipient as part of apharmaceutical composition. A “pharmaceutically acceptable carrier” is acarrier which is physiologically acceptable (e.g. physiologicallyacceptable pH) while retaining the therapeutic properties of thesubstance with which it is administered. Standard acceptablepharmaceutical carriers and their formulations are known to one skilledin the art and described, for example, in Remington: The Science andPractice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000,Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed), Handbook ofPharmaceutical excipients, PhP, May 2013 update. One exemplarypharmaceutically acceptable carrier is physiological saline solution.

In one embodiment carriers are selected from the group of buffers (e.g.citrate/citric acid), acidifying agents (e.g. hydrochloric acid),alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol),co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g.mannitol), stabilizers (e.g. surfactant, antioxidants, amino acids).

Concentrations used are in a range that is physiologically acceptable.

Acceptable pharmaceutical carriers or diluents include those used informulations suitable for oral, rectal, nasal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, and transdermal)administration. The compounds of the present invention will typically beadministered parenterally.

The term “pharmaceutically acceptable salt” means salts of the compoundsof the invention which are safe and effective for use in mammals.Pharmaceutically acceptable salts may include, but are not limited to,acid addition salts and basic salts. Examples of acid addition saltsinclude chloride, sulfate, hydrogen sulfate, (hydrogen) phosphate,acetate, citrate, tosylate or mesylate salts. Examples of basic saltsinclude salts with inorganic cations, e.g. alkaline or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts andsalts with organic cations such as amine salts. Further examples ofpharmaceutically acceptable salts are described in Remington: TheScience and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R.,2000, Lippencott Williams & Wilkins or in Handbook of PharmaceuticalSalts, Properties, Selection and Use, e.d. P. H. Stahl, C. G. Wermuth,2002, jointly published by Verlag Helvetica Chimica Acta, Zurich,Switzerland, and Wiley-VCH, Weinheim, Germany.

The term “solvate” means complexes of the compounds of the invention orsalts thereof with solvent molecules, e.g. organic solvent moleculesand/or water.

In the pharmaceutical composition, the exendin-4 derivative can be inmonomeric or oligomeric form.

The term “therapeutically effective amount” of a compound refers to anontoxic but sufficient amount of the compound to provide the desiredeffect. The amount of a compound of the formula (I) necessary to achievethe desired biological effect depends on a number of factors, forexample the specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. An appropriate“effective” amount in any individual case may be determined by one ofordinary skill in the art using routine experimentation For example the“therapeutically effective amount” of a compound of the formula (I) isabout 0.01 to 50 mg/dose, preferably 0.1 to 10 mg/dose.

Pharmaceutical compositions of the invention are those suitable forparenteral (for example subcutaneous, intramuscular, intradermal orintravenous), oral, rectal, topical and peroral (for example sublingual)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula (I)used in each case.

Suitable pharmaceutical compositions may be in the form of separateunits, for example capsules, tablets and powders in vials or ampoules,each of which contains a defined amount of the compound; as powders orgranules; as solution or suspension in an aqueous or nonaqueous liquid;or as an oil-in-water or water-in-oil emulsion. It may be provided insingle or multiple dose injectable form, for example in the form of apen. The compositions may, as already mentioned, be prepared by anysuitable pharmaceutical method which includes a step in which the activeingredient and the carrier (which may consist of one or more additionalingredients) are brought into contact.

In certain embodiments the pharmaceutical composition may be providedtogether with a device for application, for example together with asyringe, an injection pen or an autoinjector. Such devices may beprovided separate from a pharmaceutical composition or prefilled withthe pharmaceutical composition.

Combination Therapy

The compounds of the present invention, dual agonists for the GLP-1 andglucagon receptors, can be widely combined with other pharmacologicallyactive compounds, such as all drugs mentioned in the Rote Liste 2014,e.g. with all weight-reducing agents or appetite suppressants mentionedin the Rote Liste 2014, chapter 1, all lipid-lowering agents mentionedin the Rote Liste 2014, chapter 58, all antihypertensives andnephroprotectives, mentioned in the Rote Liste 2014, or all diureticsmentioned in the Rote Liste 2014, chapter 36.

The active ingredient combinations can be used especially for asynergistic improvement in action. They can be applied either byseparate administration of the active ingredients to the patient or inthe form of combination products in which a plurality of activeingredients are present in one pharmaceutical preparation. When theactive ingredients are administered by separate administration of theactive ingredients, this can be done simultaneously or successively.

Most of the active ingredients mentioned hereinafter are disclosed inthe USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2011.

Other active substances which are suitable for such combinations includein particular those which for example potentiate the therapeutic effectof one or more active substances with respect to one of the indicationsmentioned and/or which allow the dosage of one or more active substancesto be reduced.

Therapeutic agents which are suitable for combinations include, forexample, antidiabetic agents such as:

Insulin and Insulin derivatives, for example: Glargine/Lantus®, 270-330U/mL of insulin glargine (EP 2387989 A), 300 U/mL of insulin glargine(EP 2387989 A), Glulisin/Apidra®, Detemir/Levemir®,Lispro/Humalog®/Liprolog®, Degludec/DegludecPlus, Aspart, basal insulinand analogues (e.g. LY-2605541, LY2963016, NN1436), PEGylated insulinLispro, Humulin®, Linjeta, SuliXen®, NN1045, Insulin plus Symlin,PE0139, fast-acting and short-acting insulins (e.g. Linjeta, PH20,NN1218, HinsBet), (APC-002)hydrogel, oral, inhalable, transdermal andsublingual insulins (e.g. Exubera®, Nasulin®, Afrezza, Tregopil, TPM 02,Capsulin, Oral-Lyn®, Cobalamin® oral insulin, ORMD-0801, NN1953, NN1954,NN1956, VIAtab, Oshadi oral insulin). Additionally included are alsothose insulin derivatives which are bonded to albumin or another proteinby a bifunctional linker.

GLP-1, GLP-1 analogues and GLP-1 receptor agonists, for example:Lixisenatide/AVE0010/ZP10/Lyxumia,Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993,Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide,Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926,NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697,DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030,CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN andGlucagon-Xten.

DPP4 inhibitors, for example: Alogliptin/Nesina,Trajenta/Linagliptin/BI-1356/Ondero/Trajenta/Tradjenta/Trayenta/Tradzenta,Saxagliptin/Onglyza,Sitagliptin/Januvia/Xelevia/Tesave/Janumet/Velmetia,Galvus/Vildagliptin, Anagliptin, Gemigliptin, Teneligliptin,Melogliptin, Trelagliptin, DA-1229, Omarigliptin/MK-3102, KM-223,Evogliptin, ARI-2243, PBL-1427, Pinoxacin.

SGLT2 inhibitors, for example: Invokana/Canaglifozin,Forxiga/Dapagliflozin, Remoglifozin, Sergliflozin, Empagliflozin,Ipragliflozin, Tofogliflozin, Luseogliflozin, LX-4211,Ertuglifozin/PF-04971729, RO-4998452, EGT-0001442, KGA-3235/DSP-3235,LIK066, SBM-TFC-039,

Biguanides (e.g. Metformin, Buformin, Phenformin), Thiazolidinediones(e.g. Pioglitazone, Rivoglitazone, Rosiglitazone, Troglitazone), dualPPAR agonists (e.g. Aleglitazar, Muraglitazar, Tesaglitazar),Sulfonylureas (e.g. Tolbutamide, Glibenclamide, Glimepiride/Amaryl,Glipizide), Meglitinides (e.g. Nateglinide, Repaglinide, Mitiglinide),Alpha-glucosidase inhibitors (e.g. Acarbose, Miglitol, Voglibose),Amylin and Amylin analogues (e.g. Pramlintide, Symlin).

GPR119 agonists (e.g. GSK-263A, PSN-821, MBX-2982, APD-597, ZYG-19,DS-8500), GPR40 agonists (e.g. Fasiglifam/TAK-875, TUG-424, P-1736,JTT-851, GW9508).

Other suitable combination partners are: Cycloset, inhibitors of11-beta-HSD (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329,HSD-016, BI-135585), activators of glucokinase (e.g. TTP-399, AMG-151,TAK-329, GKM-001), inhibitors of DGAT (e.g. LCQ-908), inhibitors ofprotein tyrosinephosphatase 1 (e.g. Trodusquemine), inhibitors ofglucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase,inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvatecarboxykinase, inhibitors of glycogen synthase kinase, inhibitors ofpyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists, SGLT-1inhibitors (e.g. LX-2761), dual SGLT2/SGLT1 inhibitors.

One or more lipid lowering agents are also suitable as combinationpartners, such as for example: HMG-CoA-reductase inhibitors (e.g.Simvastatin, Atorvastatin), fibrates (e.g. Bezafibrate, Fenofibrate),nicotinic acid and the derivatives thereof (e.g. Niacin), PPAR-(alpha,gamma or alpha/gamma) agonists or modulators (e.g. Aleglitazar),PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe), cholesterolabsorption inhibitors (e.g. Ezetimibe), Bile acid-binding substances(e.g. Cholestyramine), ileal bile acid transport inhibitors, MTPinhibitors, or modulators of PCSK9.

HDL-raising compounds such as: CETP inhibitors (e.g. Torcetrapib,Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995) orABC1 regulators.

Other suitable combination partners are one or more active substancesfor the treatment of obesity, such as for example: Sibutramine,Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists(e.g. Velneperit), beta-3-agonists, leptin or leptin mimetics, agonistsof the 5HT2c receptor (e.g. Lorcaserin), or the combinations ofbupropione/naltrexone, bupropione/zonisamide, bupropione/phentermine orpramlintide/metreleptin.

Other suitable combination partners are:

Further gastrointestinal peptides such as Peptide YY 3-36 (PYY3-36) oranalogues thereof, pancreatic polypeptide (PP) or analogues thereof.

Glucagon receptor agonists or antagonists, GIP receptor agonists orantagonists, ghrelin antagonists or inverse agonists, Xenin andanalogues thereof.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis, such as e.g.: Angiotensin IIreceptor antagonists (e.g. telmisartan, candesartan, valsartan,losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan),ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calciumantagonists, centrally acting hypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable.

In another aspect, this invention relates to the use of a compoundaccording to the invention or a physiologically acceptable salt thereofcombined with at least one of the active substances described above as acombination partner, for preparing a medicament which is suitable forthe treatment or prevention of diseases or conditions which can beaffected by binding to the receptors for GLP-1 and glucagon and bymodulating their activity. This is preferably a disease in the contextof the metabolic syndrome, particularly one of the diseases orconditions listed above, most particularly diabetes or obesity orcomplications thereof.

The use of the compounds according to the invention, or aphysiologically acceptable salt thereof, in combination with one or moreactive substances may take place simultaneously, separately orsequentially.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; if they areused at staggered times, the two active substances are given to thepatient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to a medicamentwhich comprises a compound according to the invention or aphysiologically acceptable salt of such a compound and at least one ofthe active substances described above as combination partners,optionally together with one or more inert carriers and/or diluents.

The compound according to the invention, or physiologically acceptablesalt or solvate thereof, and the additional active substance to becombined therewith may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as so-called kit-of-parts.

Methods

Abbreviations Employed are as Follows:

-   AA amino acid-   AEEAc (2-(2-aminoethoxyl)ethoxy)acetyl-   cAMP cyclic adenosine monophosphate-   Boc tert-butyloxycarbonyl-   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   BSA bovine serum albumin-   tBu tertiary butyl-   DCM dichloromethane-   Dde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl-   ivDde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl-   DIC N,N′-diisopropylcarbodiimide-   DIPEA N,N-diisopropylethylamine-   DMEM Dulbecco's modified Eagle's medium-   DMF dimethyl formamide-   DMS dimethylsulfide-   EDT ethanedithiol-   FA formic acid-   FBS fetal bovine serum-   Fmoc fluorenylmethyloxycarbonyl-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBSS Hanks' Balanced Salt Solution-   HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium    hexafluorophosphate-   HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid-   HOBt 1-hydroxybenzotriazole-   HOSu N-hydroxysuccinimide-   HPLC High Performance Liquid Chromatography-   HTRF Homogenous Time Resolved Fluorescence-   IBMX 3-isobutyl-1-methylxanthine-   LC/MS Liquid Chromatography/Mass Spectrometry-   Mmt monomethoxy-trityl-   Palm palmitoyl-   PBS phosphate buffered saline-   PEG polyethylene glycole-   PK pharmacokinetic-   RP-HPLC reversed-phase high performance liquid chromatography-   Stea stearyl-   TFA trifluoroacetic acid-   Trt trityl-   UV ultraviolet-   γE-Glutamate    General Synthesis of Peptidic Compounds    Materials

Different Rink-Amide resins(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethylresin, Merck Biosciences;4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methylresin, Agilent Technologies) were used for the synthesis of peptideamides with loadings in the range of 0.2-0.7 mmol/g.

Fmoc protected natural amino acids were purchased from ProteinTechnologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, IrisBiotech, Bachem, Chem-Impex International or MATRIX Innovation. Thefollowing standard amino acids were used throughout the syntheses:Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH,Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH,Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Ile-OH,Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-Phe-OH,Fmoc-L-Pro-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH,Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Val-OH.

In addition, the following special amino acids were purchased from thesame suppliers as above: Fmoc-L-Lys(ivDde)-OH, Fmoc-L-Lys(Mmt)-OH,Fmoc-Aib-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Ala-OH, Boc-L-His(Boc)-OH(available as toluene solvate) and Boc-L-His(Trt)-OH.

The solid phase peptide syntheses were performed for example on aPrelude Peptide Synthesizer (Protein Technologies Inc) or similarautomated synthesizer using standard Fmoc chemistry and HBTU/DIPEAactivation. DMF was used as the solvent. Deprotection: 20%piperidine/DMF for 2×2.5 min. Washes: 7×DMF. Coupling 2:5:10 200 mMAA/500 mM HBTU/2M DIPEA in DMF 2× for 20 min. Washes: 5×DMF.

In cases where a Lys-side-chain was modified, Fmoc-L-Lys(ivDde)-OH orFmoc-L-Lys(Mmt)-OH was used in the corresponding position. Aftercompletion of the synthesis, the ivDde group was removed according to amodified literature procedure (S. R. Chhabra et al., Tetrahedron Lett.39, (1998), 1603), using 4% hydrazine hydrate in DMF. The Mmt group wasremoved by repeated treatment with 1% TFA in dichloromethane. Thefollowing acylations were carried out by treating the resin with theN-hydroxy succinimide esters of the desired acid or using couplingreagents like HBTU/DIPEA or HOBt/DIC.

All the peptides that had been synthesized were cleaved from the resinwith King's cleavage cocktail consisting of 82.5% TFA, 5% phenol, 5%water, 5% thioanisole, 2.5% EDT. The crude peptides were thenprecipitated in diethyl or diisopropyl ether, centrifuged, andlyophilized. Peptides were analyzed by analytical HPLC and checked byESI mass spectrometry. Crude peptides were purified by a conventionalpreparative HPLC purification procedure.

Alternatively, peptides were synthesized by a manual synthesisprocedure:

0.3 g Desiccated Rink amide MBHA Resin (0.66 mmol/g) was placed in apolyethylene vessel equipped with a polypropylene filter. Resin wasswelled in DCM (15 ml) for 1 h and DMF (15 ml) for 1 h. The Fmoc groupon the resin was de-protected by treating it twice with 20% (v/v)piperidine/DMF solution for 5 and 15 min. The resin was washed withDMF/DCM/DMF (6:6:6 time each). A Kaiser test (quantitative method) wasused for the conformation of removal of Fmoc from solid support. TheC-terminal Fmoc-amino acid (5 equiv. excess corresponding to resinloading) in dry DMF was added to the de-protected resin and coupling wasinitiated with 5 equivalent excess of DIC and HOBt in DMF. Theconcentration of each reactant in the reaction mixture was approximately0.4 M. The mixture was rotated on a rotor at room temperature for 2 h.Resin was filtered and washed with DMF/DCM/DMF (6:6:6 time each). Kaisertest on peptide resin aliquot upon completion of coupling was negative(no colour on the resin). After the first amino acid attachment, theunreacted amino group, if any, in the resin was capped used aceticanhydride/pyridine/DCM (1:8:8) for 20 minutes to avoid any deletion ofthe sequence. After capping, resin was washed with DCM/DMF/DCM/DMF(6/6/6/6 time each). The Fmoc group on the C-terminal amino acidattached peptidyl resin was deprotected by treating it twice with 20%(v/v) piperidine/DMF solution for 5 and 15 min. The resin was washedwith DMF/DCM/DMF (6:6:6 time each). The Kaiser test on peptide resinaliquot upon completion of Fmoc-deprotection was positive.

The remaining amino acids in target sequence on Rink amide MBHA Resinwere sequentially coupled using Fmoc AA/DIC/HOBt method using 5equivalent excess corresponding to resin loading in DMF. Theconcentration of each reactant in the reaction mixture was approximately0.4 M. The mixture was rotated on a rotor at room temperature for 2 h.Resin was filtered and washed with DMF/DCM/DMF (6:6:6 time each). Aftereach coupling step and Fmoc deprotection step, a Kaiser test was carriedout to confirm the completeness of the reaction.

After the completion of the linear sequence, the ε-amino group of lysineused as branching point or modification point was deprotected by using2.5% hydrazine hydrate in DMF for 15 min×2 and washed with DMF/DCM/DMF(6:6:6 time each). The γ-carboxyl end of glutamic acid was attached tothe ε-amino group of Lys using Fmoc-Glu(OH)-OtBu with DIC/HOBt method (5equivalent excess with respect to resin loading) in DMF. The mixture wasrotated on a rotor at room temperature for 2 h. The resin was filteredand washed with DMF/DCM/DMF (6×30 ml each). The Fmoc group on theglutamic acid was de-protected by treating it twice with 20% (v/v)piperidine/DMF solution for 5 and 15 min (25 ml each). The resin waswashed with DMF/DCM/DMF (6:6:6 time each). A Kaiser test on peptideresin aliquot upon completion of Fmoc-deprotection was positive.

If the side-chain branching also contains one more γ-glutamic acid, asecond Fmoc-Glu(OH)-OtBu used for the attachment to the free amino groupof γ-glutamic acid with DIC/HOBt method (5 equivalent excess withrespect to resin loading) in DMF. The mixture was rotated on a rotor atroom temperature for 2 h. Resin was filtered and washed with DMF/DCM/DMF(6×30 ml each). The Fmoc group on the γ-glutamic acid was de-protectedby treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15min (25 mL). The resin was washed with DMF/DCM/DMF (6:6:6 time each). AKaiser test on peptide resin aliquot upon completion ofFmoc-deprotection was positive.

Palmitic Acid & Stearic Acid Attachment to Side Chains of Glutamic Acid:

To the free amino group of γ-glutamic acid, palmitic acid or stearicacid (5 equiv.) dissolved in DMF was added and coupling was initiated bythe addition of DIC (5 equiv.) and HOBt (5 equiv.) in DMF. The resin waswashed with DMF/DCM/DMF (6:6:6 time each).

Final Cleavage of Peptide from the Resin:

The peptidyl resin synthesized by manual synthesis was washed with DCM(6×10 ml), MeOH (6×10 ml) and ether (6×10 ml) and dried in vacuumdesiccators overnight. The cleavage of the peptide from the solidsupport was achieved by treating the peptide-resin with reagent cocktail(80.0% TFA/5% thioanisole/5% phenol/2.5% EDT, 2.5% DMS and 5% DCM) atroom temperature for 3 h. Cleavage mixture was collected by filtrationand the resin was washed with TFA (2 ml) and DCM (2×5 ml). The excessTFA and DCM was concentrated to small volume under nitrogen and a smallamount of DCM (5-10 ml) was added to the residue and evaporated undernitrogen. The process was repeated 3-4 times to remove most of thevolatile impurities. The residue was cooled to 0° C. and anhydrous etherwas added to precipitate the peptide. The precipitated peptide wascentrifuged and the supernatant ether was removed and fresh ether wasadded to the peptide and re-centrifuged. The crude sample waspreparative HPLC purified and lyophilized. The identity of peptide wasconfirmed by LCMS.

Analytical HPLC/UPLC

Method A:

-   detection at 210-225 nm-   column: Waters ACQUITY UPLC® BEH™ C18 1.7 μm (150×2.1 mm) at 50° C.-   solvent: H2O+1% FA: ACN+1% FA (flow 0.6 ml/min)-   gradient: 95:5 (0 min) to 95:5 (1 min) to 35:65 (3 min) to 55:45 (23    min) to 5:95 (24 min) to 75:5 (25 min) to 95:5 (30 min)-   optionally with mass analyser: LCT Premier, electrospray positive    ion mode    Method B:-   detection at 210-225 nm-   column: Waters ACQUITY UPLC® CSH™ C18 1.7 μm (150×2.1 mm) at 50° C.-   solvent: H₂O+0.5% TFA: ACN+0.35% TFA (flow 0.5 ml/min)-   gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98    (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min)-   optionally with mass analyser: LCT Premier, electrospray positive    ion mode    Method C:-   detection at 220 nm-   column: YMC-PACK-ODS-A, C18 (10×250 mm, 5 μm), 25° C.-   solvent: H₂O+0.1% TFA: ACN+0.1% TFA (flow 1 ml/min)-   gradient: 0-2 min=20-30% buffer B, 2-30 min=30-60% buffer B    Method D:-   detection at 220 nm-   column: Phenomenex Kinetich, C18 (2), (20×250 mm, 5 μm), 25° C.-   solvent: H₂O+0.1% TFA: ACN+0.1% TFA (flow 1 ml/min)-   gradient: 0-2 min=2% buffer B, 2-5 min=2-20% buffer B, 5-11.5    min=20-27% buffer B, 11.5-35 min=27% buffer B, 35-35.01 min=27-100%    buffer B with a flow rate of 20 mL/min.    General Preparative HPLC Purification Procedure

The crude peptides were purified either on an Äkta Purifier System, aJasco semiprep HPLC System or a Agilent 1100 HPLC system. PreparativeRP-C18-HPLC columns of different sizes and with different flow rateswere used depending on the amount of crude peptide to be purified.Acetonitrile+0.1% TFA (B) and water+0.1% TFA (A) were employed aseluents. Product-containing fractions were collected and lyophilized toobtain the purified product, typically as TFA salt.

Solubility and Stability-Testing of Exendin-4 Derivatives

Prior to the testing of solubility and stability of a peptide batch, itspurity (HPLC-UV) was determined.

For solubility testing, the target concentration was 10 mg purecompound/ml.

Therefore, solutions from solid samples were prepared in differentbuffer systems with a concentration of 10 mg/mL compound based on thepreviously determined % purity. HPLC-UV was performed after 2 h ofgentle agitation from the supernatant, which was obtained by 20 min ofcentrifugation at 4500 rpm.

The solubility was then determined by comparison of a 0.2 μL-injectionwith the UV peak areas obtained with a stock solution of the peptide ata concentration of 1.2 mg/mL in DMSO (based on % purity), injectingvarious volumes ranging from 0.2-2 μl. This analysis also served asstarting point (t0) for the stability testing.

For stability testing, an aliquot of the supernatant obtained forsolubility was stored for 7 days at 40° C. After that time course, thesample was centrifuged for 20 min at 4500 rpm and 0.2 μL of thesupernatant were analysed with HPLC-UV.

For determination of the amount of the remaining peptide, the peak areasof the target compound at t0 and t7 were compared, resulting in “%remaining peptide”, following the equation% remaining peptide=[(peak area peptide t7)×100]/peak area peptide t0.

The stability is expressed as “% remaining peptide”.

As HPLC/UPLC method Method B has been used, detecting at 214 nm.

In Vitro Cellular Assays for GLP-1 Receptor, Glucagon Receptor and GIPReceptor Efficacy

Agonism of compounds for the receptors was determined by functionalassays measuring cAMP response of HEK-293 cell lines stably expressinghuman GLP-1, glucagon or GIP receptor.

cAMP content of cells was determined using a kit from Cisbio Corp. (cat.no. 62AM4PEC) based on HTRF (Homogenous Time Resolved Fluorescence). Forpreparation, cells were split into T175 culture flasks and grownovernight to near confluency in medium (DMEM/10% FBS). Medium was thenremoved and cells washed with PBS lacking calcium and magnesium,followed by proteinase treatment with accutase (Sigma-Aldrich cat. no.A6964). Detached cells were washed and resuspended in assay buffer(1×HBSS; 20 mM HEPES, 0.1% BSA, 2 mM IBMX) and cellular densitydetermined. They were then diluted to 400000 cells/ml and 25 μl-aliquotsdispensed into the wells of 96-well plates. For measurement, 25 μl oftest compound in assay buffer was added to the wells, followed byincubation for 30 minutes at room temperature. After addition of HTRFreagents diluted in lysis buffer (kit components), the plates wereincubated for 1 hr, followed by measurement of the fluorescence ratio at665/620 nm. In vitro potency of agonists was quantified by determiningthe concentrations that caused 50% activation of maximal response(EC50).

Bioanalytical Screening Method for Quantification of Exendin-4Derivatives in Mice

Mice are dosed 1 mg/kg subcutaneously (s.c.). The mice are sacrificedand blood samples are collected after 0.25, 0.5, 1, 2, 4, 8, 16 and 24hours post application. Plasma samples are analyzed after proteinprecipitation via liquid chromatography mass spectrometry (LC/MS). PKparameters and half-life were calculated using WinonLin Version 5.2.1(non-compartment model).

Gastric Emptying and Intestinal Passage in Mice

Female NMRI-mice of a body weight between 20 and 30 g are used. Mice areadapted to housing conditions for at least one week.

Mice are overnight fasted, while water remains available all the time.On the study day, mice are weighed, single-caged and allowed access to500 mg of feed for 30 min, while water is removed. At the end of the 30min feeding period, remaining feed is removed and weighed. 60 min later,a coloured, non-caloric bolus is instilled via gavage into the stomach.The test compound/reference compound or its vehicle in the control groupis administered subcutaneously, to reach Cmax when coloured bolus isadministered. After another 30 min, the animals are sacrificed and thestomach and the small intestine prepared. The filled stomach is weighed,emptied, carefully cleaned and dried and reweighed. The calculatedstomach content indicates the degree of gastric emptying. The smallintestine is straightened without force and measured in length. Then thedistance from the gastric beginning of the gut to the tip of thefarthest traveled intestinal content bolus is measured. The intestinalpassage is given as relation in percent of the latter distance and thetotal length of the small intestine.

Comparable data can be obtained for both female and male mice.

Statistical analyses are performed with Everstat 6.0 by 1-way-ANOVA,followed by Dunnetts or Newman-Keuls as post-hoc test, respectively.Differences are considered statistically significant at the p<0.05level. As post hoc test Dunnet's Test is applied to compare versusvehicle control, only. Newman-Keul's Test is applied for all pairwisecomparisons (i.e. versus vehicle and reference groups).

Automated Assessment of Feed Intake in Mice

Female NMRI-mice of a body weight between 20 and 30 g are used. Mice areadapted to housing conditions for at least one week and for at least oneday single-caged in the assessment equipment, when basal data arerecorded simultaneously. On the study day, test product is administeredsubcutaneously close to the lights-off phase (12 h lights off) andassessment of feed consumption is directly started afterwards.Assessment included continued monitoring (every 30 min) over 22 hours.Repetition of this procedure over several days is possible. Restrictionof assessment to 22 hours is for practical reasons to allow forreweighing of animals, refilling of feed and water and drugadministration between procedures. Results can be assessed as cumulateddata over 22 hours or differentiated to 30 min intervals.

Comparable data can be obtained for both female and male mice.

Statistical analyses are performed with Everstat 6.0 by two-way ANOVA onrepeated measures and Dunnett's post-hoc analyses. Differences areconsidered statistically significant at the p<0.05 level.

Acute and Chronic Effects after Subcutaneous Treatment on Blood Glucoseand Body Weight in Female Diet-Induced Obese (DIO) C57BL/6 Mice

C57BL/6 Harlan mice are housed in groups in a specific pathogen-freebarrier facility on a 12 h light/dark cycle with free access to waterand standard or high-fat diet. After prefeeding on high-fat diet, miceare stratified to treatment groups (n=8), so that each group has similarmean body weight. An age-matched group with ad-libitum access tostandard chow is included as standard control group. Before theexperiment, mice are subcutaneously (s.c.) injected with vehiclesolution and weighed for 3 days to acclimate them to the procedures.

1) Acute effect on blood glucose in fed female DIO mice: initial bloodsamples are taken just before first administration (s.c.) of vehicle(phosphate buffer solution) or the exendin-4 derivatives (dissolved inphosphate buffer), respectively. The volume of administration is 5mL/kg. The animals have access to water and their corresponding dietduring the experiment. Blood glucose levels are measured at t=0 h, t=1h, t=2 h, t=3 h, t=4 h, t=6 h and t=24 h (method: Accu-Checkglucometer). Blood sampling is performed by tail incision withoutanaesthesia.

2) Chronic effect on body weight in female DIO mice: mice are treatedtwice daily s.c. in the morning and in the evening, respectively, at thebeginning and the end of the light phase with either vehicle orexendin-4 derivatives for 4 weeks. Body weight is recorded daily. Twodays before start of treatment and on day 26, total fat mass is measuredby nuclear magnetic resonance (NMR).

Statistical analyses are performed with Everstat 6.0 by repeatedmeasures two-way ANOVA and Dunnetts post-hoc analyses (glucose profile)and 1-way-ANOVA, followed by Dunnetts post-hoc test (body weight, bodyfat). Differences versus vehicle-treated DIO control mice are consideredstatistically significant at the p<0.05 level.

Effects of 4 Weeks of Treatment on Glucose, HbA1c and Oral GlucoseTolerance in Female Diabetic dbdb-Mice (Method 4)

8 week old, female diabetic dbdb-mice of mean non-fasted glucose valueof 14.5 mmol/l and a body weight of 37-40 g are used. Mice areindividually marked and are adapted to housing conditions for at leastone week.

7 days prior to study start, baseline values for non-fasted glucose andHbA1c are determined, 5 days prior to study start, mice are assigned togroups and cages (5 mice per cage, 10 per group) according to theirHbA1c values to ensure even distribution of lower and higher valuesbetween groups (stratification).

Mice are treated for 4 weeks, by twice daily subcutaneous administrationin the morning and the afternoon. Blood samples from the tail tip areobtained for HbA1c on study day 21 and oral glucose tolerance isassessed in the 4th week.

An oral glucose tolerance test is done in the morning without priorextra compound administration to majorly assess the effect of chronictreatment and less of acute compound administration. Mice are fasted for4 hours prior to oral glucose administration (2 g/kg, t=0 min). Bloodsamples are drawn prior to glucose administration and at 15, 30, 60, 90,120, and 180 min. Feed is returned after the last blood sampling.Results are represented as change from baseline, glucose in mmol/l andHbA1c in %.

Statistical analyses are performed with Everstat Version 6.0 based onSAS by 1-way-ANOVA, followed by Dunnett's post-hoc test againstvehicle-control. Differences are considered statistically significant atthe p<0.05 level.

Glucose Lowering in Non-Fasted Female Diabetic dbdb-Mice

Female diabetic dbdb-mice of mean non-fasted glucose value of 20-22mmol/l and a body weight of 42 g+/−0.6 g (SEM) are used. Mice areindividually marked and are adapted to housing conditions for at leastone week.

3-5 days prior to study start mice are assigned to groups and cages (4mice per cage, 8 per group) according to their non-fasted glucose valuesto ensure even distribution of lower and higher values between groups(stratification). On the study day, mice are weighed and dosed (t=0).Immediately prior to compound administration feed is removed while waterremains available, and a first blood sample at a tail incision is drawn(baseline). Further blood samples are drawn at the tail incision at 30,60, 90, 120, 240, 360, and 480 min.

Statistical analyses are performed with Everstat Version 6.0 based onSAS by 2-way-ANOVA on repeated measures, followed by Dunnett's post-hoctest against vehicle-control. Differences are considered statisticallysignificant at the p<0.05 level.

EXAMPLES

The invention is further illustrated by the following examples.

Example 1: Synthesis of SEQ ID NO: 8

The manual synthesis procedure as described in Methods was carried outon a desiccated Rink amide MBHA Resin (0.66 mmol/g). The Fmoc-synthesisstrategy was applied with DIC/HOBt-activation. In position 14Fmoc-Lys(ivDde)-OH and in position 1 Boc-His(Boc)-OH were used. TheivDde-group was cleaved from the peptide on resin according to amodified literature procedure (S. R. Chhabra et al., Tetrahedron Lett.39, (1998), 1603), using 4% hydrazine hydrate in DMF. The peptide wascleaved from the resin with King's cocktail (D. S. King, C. G. Fields,G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crudeproduct was purified via preparative RP-HPLC using an acetonitrile/watergradient (both buffers with 0.1% TFA). The purified peptide was analysedby LCMS (Method C). Deconvolution of the mass signals found under thepeak with retention time 12.66 min revealed the peptide mass 4557.6which is in line with the expected value of 4558.22.

Example 2: Synthesis of SEQ ID NO: 11

The manual synthesis procedure as described in Methods was carried outon a desiccated Rink amide MBHA Resin (0.66 mmol/g). The Fmoc-synthesisstrategy was applied with DIC/HOBt-activation. In position 14Fmoc-Lys(ivDde)-OH and in position 1 Boc-His(Boc)-OH were used. TheivDde-group was cleaved from the peptide on resin according to amodified literature procedure (S. R. Chhabra et al., Tetrahedron Lett.39, (1998), 1603), using 4% hydrazine hydrate in DMF. The peptide wascleaved from the resin with King's cocktail (D. S. King, C. G. Fields,G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crudeproduct was purified via preparative RP-HPLC using an acetonitrile/watergradient (both buffers with 0.1% TFA). The purified peptide was analysedby LCMS (Method D). Deconvolution of the mass signals found under thepeak with retention time 14.40 min revealed the peptide mass 4673.6which is in line with the expected value of 4673.32.

In an analogous way, the following peptides SEQ ID NO: 6, 7, 9, 10 and12-29 and 31-35 were synthesized and characterized (Method A-D), seeTable 3.

TABLE 3 list of synthesized peptides and comparison of calculated vs.found molecular weight. SEQ calc. found Monoisotopic ID NO Mass mass oraverage mass 6 4563.2 4561.6 Average 7 4572.2 4571.6 Average 8 4558.24557.6 Average 9 4574.2 4574.7 Average 10 4574.2 4573.7 Average 114673.3 4673.6 Average 12 4544.2 4543.2 Average 13 4675.3 4676.1 Average14 4546.2 4546.2 Average 15 4560.2 4560.0 Average 16 4565.2 4564.5Average 17 4622.3 4621.3 Average 18 4537.2 4536.4 Average 19 4551.24550.7 Average 20 4565.2 4564.4 Average 21 4661.3 4660.6 Average 224666.3 4665.4 Average 23 4649.4 4649.2 Monoisotopic 24 4664.3 4662.9Average 25 4574.2 4573.7 Average 26 4663.4 4663.39 Monoisotopic 274831.5 4831.60 Monoisotopic 28 4859.6 4859.70 Monoisotopic 29 4875.44875.70 Monoisotopic 31 4727.5 4727.5 Monoisotopic 32 4179.7 4178.7Average 33 4181.7 4181.4 Average 34 4218.7 4217.7 Average 35 4220.74220.1 Average

In an analogous way, the following peptides of Table 4 can besynthesized:

TABLE 4 List of peptides that can be synthesized in an analogous way.SEQ ID NO 30

Example 3: Stability and Solubility

Solubility and stability of peptidic compounds were assessed asdescribed in Methods. The results are given in Table 5.

TABLE 5 Stability and solubility Stability Stability SolubilitySolubility SEQ (pH 4.5) (pH 7.4) (pH 4.5) (pH 7.4) ID NO: [%] [%][μg/ml] [μg/ml] 1 100.0 77.5 933.6 1000 (Exendin-4) 9 — — >5000 >5000 1092.7 93.4 >5000 >5000 11 97.5 95.8 >5000 >5000 12 96.7 92.0 >5000 >500016 94.0 98.0 >5000 >5000 20 95.6 95.2 >5000 >5000

Example 4: In Vitro Data on GLP-1, GIP and Glucagon Receptor

Potencies of peptidic compounds at the GLP-1, glucagon and GIP receptorswere determined by exposing cells expressing human glucagon receptor(hGCG R), human GIP (hGIP R) and human GLP-1 receptor (hGLP-1 R) to thelisted compounds at increasing concentrations and measuring the formedcAMP as described in Methods.

The results for Exendin-4 derivatives with activity at the human GLP-1receptor (hGLP-1 R), human glucagon receptor (hGCG R) and human GIP(hGIP R) are shown in Table 6.

TABLE 6 EC50 values of exendin-4 peptide analogues at GLP-1, glucagonand GIP receptors (indicated in pM) SEQ EC50 EC50 EC50 ID NO hGLP-1RhGlucagon-R hGIP-R 1 0.4 >10000000 12500.0 6 9.4 309.0 60.7 7 6.5 5.825.6 8 4.5 24.5 25.8 9 4.0 24.9 475.0 10 3.4 6.9 71.1 11 1.4 8.9 7.9 123.3 12.8 8.8 13 1.4 22.5 79.0 14 4.1 58.4 437.0 15 4.4 64.0 555.0 16 4.565.2 527.0 17 8.6 79.2 1420.0 18 3.0 225.0 747.0 19 3.5 129.0 400.0 203.7 11.7 28.1 21 0.8 85.9 99.4 22 1.9 81.6 143.0 23 1.2 124.0 350.0 244.5 261.0 19.9 25 8.1 39.9 407.0 26 1.4 18.7 44.7 27 1.4 23.4 9.5 28 3.817.1 17.0 29 4.7 17.9 47.6

Example 5: Comparison Testing

A selection of inventive exendin-4 derivatives comprising afunctionalized amino acid with a lipophilic attachment in position 14has been tested versus corresponding compounds having in this position14 a ‘non-functionalized’ amino acid or an acetylated lysine residuewith otherwise identical amino acid sequence. The reference paircompounds and the corresponding EC50 values at GLP-1, glucagon and GIPreceptors (indicated in pM) are given in Table 7. As shown, theinventive exendin-4 derivatives show a superior activity on the glucagonreceptor in comparison to the compounds with a ‘non-functionalized’amino acid or an acetylated lysine in position 14.

TABLE 7 Comparison of exendin-4 derivatives comprising anon-functionalized amino acid in position 14 vs. exendin-4 derivativescomprising a functionalized amino acid in position 14 with otherwiseidentical amino acid sequence. EC50 values at GLP-1, glucagon and GIPreceptors are indicated in pM. (K = lysine, M = methionine, E-x53 =(S)-4-Carboxy-4-hexadecanoylamino-butyryl-, E-x70 =(S)-4-Carboxy-4-octadecanoylamino-butyryl-, Ac = acetate, E-E-x53 =(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-) SEQ EC50 EC50 EC50 residue inID NO hGLP-1R hGlucagon-R hGIP-1 position 14 32 0.6 406.0 12.7 M 34 0.7828.5 25.4 K(Ac) 7 6.5 5.8 25.6 K(γE-x70) 11 1.4 8.9 7.9 K(γE-γE-x53) 123.3 12.8 8.8 K(γE-x53) 33 0.6 1480.0 1930.0 M 35 0.4 2860.0 4040.0 K(Ac)13 1.4 22.5 79.0 K(γE-γE-x53) 14 4.1 58.4 437.0 K(γE-x53) 25 8.1 39.9407.0 K(γE-x70)

Example 6: Pharmacokinetic Testing in Mice

Pharmacokinetic profiles were determined as described in Methods.Calculated T_(1/2) and Cmax values are shown in Table 8.

TABLE 8 Pharmacokinetic profiles of exendin-4 derivatives in mice. SEQID NO T_(1/2) [h] Cmax [ng/ml] 11 3.3 3510 20 4.5 4020

TABLE 9 Sequences SEQ. ID Sequence  1H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P- P-P-S-NH2  2H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A- A-K-E-F-I-A-W-L-V-K-G-R-NH2  3H-S-Q-G-T-F-T-S-D-Y-S-K-Y-L-D-S-R-R- A-Q-D-F-V-Q-W-L-M-N-T-OH  4H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K(γE-x53)-E-F-I-A-W-L-V-R-G-R-G-OH  5Y-A-E-G-T-F-I-S-D-Y-S-I-A-M-D-K-I-H-Q-Q-D-F-V-N-W-L-L-A-Q-K-G-K-K-N-D-W- K-H-N-I-T-Q-OH  6H-Aib-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2  7 H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K- A-G-G-P-S-S-G-A-P-P-P-S-NH2  8H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K (γE-x70)-D-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2  9 H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K- A-G-G-P-S-S-G-A-P-P-P-S-NH2 10H-S-H-G-T-F-T-S-D-L-S-K-Q-K (γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 11 H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(γE-γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L- K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 12H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K (γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 13 H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(γE-γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L- K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 14H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K (γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 15 H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-D-E-E-A-V-R-L-F-I-E-W-L-K- A-G-G-P-S-S-G-A-P-P-P-S-NH2 16H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 17 H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K- K-G-G-P-S-S-G-A-P-P-P-S-NH2 18H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 19 H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-D-E-E-A-V-R-L-F-I-E-W-L-K- A-G-G-P-S-S-G-A-P-P-P-S-NH2 20H-S-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 21 H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(γE-γE-x53)-D-E-E-A-V-R-L-F-I-E-W-L- K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 22H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 23 H-dSer-Q-G-T-F-T-S-D-L-S-K-Q-K(γE-γE-x53)-D-E-E-A-V-R-L-F-I-E-W-L- K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 24H-Aib-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 25 H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(γE-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K- A-G-G-P-S-S-G-A-P-P-P-S-NH2 26H-S-Q-G-T-F-T-S-D-L-S-K-Q-K (γE-γE-x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 27 H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(AEEAc-AEEAc E-x53)-E-E-E-A-V-R-L-F-I-E-W-L- K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 28H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(AEEAc-AEEAc- E-x70)-E-E-E-A-V-R-L-F-I-E-W- L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 29H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(AEEAc- AEEAc-AEEAc-x70)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 30H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(AEEAc-AEEAc- E-x99)-E-E-E-A-V-R-L-F-I-E-W- L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 31H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(γE-γE- x53)-E-E-E-A-V-R-L-F-I-E-W-L-K-K-G-G-P-S-S-G-A-P-P-P-S-NH2 32 H-Aib-H-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A- P-P-P-S-NH2 33H-dSer-H-G-T-F-T-S-D-L-S-K-Q-M-E-E- E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 34 H-Aib-H-G-T-F-T-S-D-L-S-K-Q-K(Ac)-E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S- G-A-P-P-P-S-NH2 35H-dSer-H-G-T-F-T-S-D-L-S-K-Q-K(Ac)- E-E-E-A-V-R-L-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2

The invention claimed is:
 1. A peptidic compound having the formula (I):(I) H₂N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-R¹

or a salt or solvate thereof, wherein X2 is an amino acid residueselected from the group consisting of Ser, D-Ser, and Aib, X3 is anamino acid residue selected from the group consisting of Gln and His,X14 is an amino acid residue with a functionalized —NH₂ side chain groupselected from the group consisting of Lys, Orn, Dab, and Dap, whereinthe —NH₂ side chain group is functionalized by —Z—C(O)—R⁵, wherein Z isa linker comprising 1-5 amino acid linker groups selected from the groupconsisting of γ-glutamate (γE) and AEEAc and combinations thereof in allstereoisomeric forms, R⁵ is a moiety comprising up to 50 carbon atomsand heteroatoms selected from the group consisting of N and O, X15 is anamino acid residue selected from the group consisting of Glu and Asp,X28 is an amino acid residue selected from the group consisting of Alaand Lys, and R¹ is NH₂ or OH.
 2. The compound or salt or solvate thereofof claim 1, wherein R¹ is NH₂.
 3. The compound or salt or solvatethereof of claim 1, wherein the peptidic compound has a relativeactivity of at least 0.1% compared to that of natural glucagon at theglucagon receptor.
 4. The compound or salt or solvate thereof of claim1, wherein the peptidic compound exhibits a relative activity of atleast 0.1% compared to that of GLP-1 (7-36)-amide at the GLP-1 receptor.5. The compound or salt or solvate thereof of claim 1, wherein X14 isLys wherein the —NH₂ side chain group is functionalized with a group—Z—C(O)R⁵, wherein Z is a group selected from the group consisting ofγE, γE-γE, AEEAc-AEEAc-γE, and AEEAc-AEEAc-AEEAc, and R⁵ is a groupselected from the group consisting of pentadecanyl, heptadecanyl, and16-carboxy hexadecanyl.
 6. The compound or salt or solvate thereof ofclaim 5, wherein X14 is Lys wherein the —NH₂ side chain group isfunctionalized with a group —Z—C(O)R⁵, wherein Z is a group selectedfrom the group consisting of γE, γE-γE, AEEAc-AEEAc-γE, andAEEAc-AEEAc-AEEAc, and R⁵ is a group selected from the group consistingof pentadecanyl and heptadecanyl.
 7. The compound or salt or solvatethereof of claim 1, wherein X2 is Ser, X3 is an amino acid residueselected from the group consisting of Gln and His, X14 is Lys whereinthe —NH₂ side chain group is functionalized by a group selected from thegroup consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,X15 is Glu, X28 is Ala, and R¹ is NH₂.
 8. The compound or salt orsolvate thereof of claim 1, wherein X2 is D-Ser, X3 is an amino acidresidue selected from the group consisting of Gln and His, X14 is Lyswherein the —NH₂ side chain group is functionalized by a group selectedfrom the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl- and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is an amino acid residue selected from the group consistingof Ala and Lys, and R¹ is NH₂.
 9. The compound or salt or solvatethereof of claim 1, wherein X2 is Aib, X3 is an amino acid residueselected from the group consisting of Gln and His, X14 is Lys whereinthe —NH₂ side chain group is functionalized by a group selected from thegroup consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,and[2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is an amino acid residue selected from the group consistingof Ala and Lys, and R¹ is NH₂.
 10. The compound or salt or solvatethereof of claim 1, wherein X2 is an amino acid residue selected fromthe group consisting of Ser, D-Ser, and Aib, X3 is Gln, X14 is Lyswherein the —NH₂ side chain group is functionalized by a group selectedfrom the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-, and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is an amino acid residue selected from the group consistingof Ala and Lys, and R¹ is NH₂.
 11. The compound or salt or solvatethereof of claim 1, wherein X2 is an amino acid residue selected fromthe group consisting of Ser, D-Ser, and Aib, X3 is His, X14 is Lyswherein the —NH₂ side chain group is functionalized by a group selectedfrom the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,and[2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is an amino acid residue selected from the group consistingof Ala and Lys, and R¹ is NH₂.
 12. The compound or salt or solvatethereof of claim 1, wherein X2 is an amino acid residue selected fromthe group consisting of Ser, D-Ser, and Aib, X3 is an amino acid residueselected from the group consisting of Gln and His, X14 is Lys whereinthe —NH₂ side chain group is functionalized by a group selected from thegroup consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,and[2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,X15 is Glu, X28 is an amino acid residue selected from the groupconsisting of Ala and Lys, and R¹ is NH₂.
 13. The compound or salt orsolvate thereof of claim 1, wherein X2 is an amino acid residue selectedfrom the group consisting of D-Ser and Aib, X3 is an amino acid residueselected from the group consisting of Gln and His, X14 is Lys whereinthe —NH₂ side chain group is functionalized by a group selected from thegroup consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,X15 is Asp, X28 is Ala, and R¹ is NH₂.
 14. The compound or salt orsolvate thereof of claim 1, wherein X2 is an amino acid residue selectedfrom the group consisting of Ser, D-Ser, and Aib, X3 is an amino acidresidue selected from the group consisting of Gln and His, X14 is Lyswherein the —NH₂ side chain group is functionalized by a group selectedfrom the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,(2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,and[2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is Ala, and R¹ is NH₂.
 15. The compound or salt or solvatethereof of claim 1, wherein X2 is an amino acid residue selected fromthe group consisting of D-Ser and Aib, X3 is an amino acid residueselected from the group consisting of Gln and His, X14 is Lys whereinthe —NH₂ side chain group is functionalized by a group selected from thegroup consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,X15 is Glu, X28 is Lys, and R¹ is NH₂.
 16. The compound or salt orsolvate thereof of claim 1, wherein X2 is Aib, X3 is His, X14 is Lyswherein the —NH₂ side chain group is functionalized by a group selectedfrom the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-, and(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl,X15 is an amino acid residue selected from the group consisting of Gluand Asp, X28 is Ala, and R¹ is NH₂.
 17. The compound or salt or solvatethereof of claim 1, selected from any one of the compounds of SEQ IDNOs: 6-31.
 18. The compound or salt or solvate thereof of claim 17,selected from any one of the compounds of SEQ ID NOs: 6-29 and
 31. 19.The compound, salt or solvate of claim 1, consisting of the amino acidsequence of SEQ ID NO: 11, or a salt or solvate thereof.
 20. Thecompound, salt or solvate of claim 1, consisting of the amino acidsequence of SEQ ID NO: 12, or a salt or solvate thereof.
 21. Thecompound, salt or solvate of claim 1, consisting of the amino acidsequence of SEQ ID NO: 20, or a salt or solvate thereof.
 22. A solvateof a compound of claim
 1. 23. A hydrate of a compound of claim
 1. 24. Apharmaceutical composition comprising one or more compounds of claim 1or a salt or solvate thereof as an active ingredient and at least onepharmaceutically acceptable carrier.
 25. The pharmaceutical compositionof claim 24, further comprising at least one additional therapeuticallyactive agent, wherein the additional therapeutically active agent isselected from the group consisting of: insulin and insulin derivativesselected from the group consisting of: insulin glargine, insulinglusiline, insulin detemir, insulin lispro, insulin degludec, insulinaspart, basal insulin and analogues thereof, pegylated insulin,recombinant human insulin, polysialated insulins, long-acting insulin,NN1045, insulin in combination with pramlintide, PE0139, fast-acting andshort-acting insulins, insulin hydrogel, oral insulin, inhalableinsulin, transdermal insulin and sublingual insulin, and insulinderivatives which are bonded to albumin or another protein by abifunctional linker; GLP-1, GLP-1 analogues, and GLP-1 receptor agonistsselected from the group consisting of: lixisenatide, exenatide,exendin-4, ITCA 650, AC-2993, liraglutide, semaglutide, taspoglutide,albiglutide, dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide, HM-11260C, CM-3, ORMD-0901, NN-9924, NN-9926, NN-9927,CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929,ZP-3022, TT-401, BHM-034, MOD-6030, CAM-2036, DA-15864, ARI-2651,ARI-2255, xtenylated exenatide, xtenylated glucagon, and polymer boundderivatives thereof; dual GLP-1/GIP receptor agonists; dualGLP-1/glucagon receptor agonists; protein YY₃₋₃₆ (PYY3-36); pancreaticpolypeptide; glucagon receptor agonists; GIP receptor agonists orantagonists; ghrelin receptor antagonists or inverse agonists; xenin;dipeptidyl peptidase IV (DPP-IV) inhibitors; sodium glucosecotransporter 2 (SGLT2) inhibitors; dual SGLT2/SGLT1 inhibitors;biguanides; thiazolidinediones; dual peroxisome proliferator-activatedreceptor (PPAR) agonists; sulfonylureas; meglitinides; alpha-glucosidaseinhibitors; amylin; pramlintide; G protein-coupled receptor 119 (GPR119)agonists; GPR40 agonists; GPR120 agonists; GPR142 agonists; systemic orlow-absorbable transmembrane G protein-coupled receptor 5 (TGR5)agonists; bromocriptine mesylate; inhibitors of 11-beta-hydroxysteroiddehydrogenase (HSD); activators of glucokinase; inhibitors ofdiacylglycerol acyltransferase (DGAT); inhibitors of proteintyrosinephosphatase 1; inhibitors of glucose-6-phosphatase; inhibitorsof fructose-1,6-bisphosphatase; inhibitors of glycogen phosphorylase;inhibitors of phosphoenol pyruvate carboxykinase; inhibitors of glycogensynthase kinase; inhibitors of pyruvate dehydrogenase kinase;alpha2-antagonists; C-C motif receptor (CCR-2) antagonists; modulatorsof glucose transporter-4; somatostatin receptor 3 agonists;3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitors;fibrates; nicotinic acid and derivatives thereof; nicotinic acidreceptor 1 agonists; PPAR-alpha, gamma, or alpha/gamma agonists ormodulators; PPAR-delta agonists; acyl-CoA cholesterol acyltransferase(ACAT) inhibitors; cholesterol absorption inhibitors; bile acid-bindingsubstances; ileal bile acid transporter (IBAT) inhibitors; microsomaltriglyceride transfer protein (MTP) inhibitors; modulators of proproteinconvertase subtilisin/kinexin type 9 (PCSK9); low-density lipoprotein(LDL) receptor up-regulators by liver selective thyroid hormone receptorβ agonists; high-density lipoprotein (HDL)-raising compounds; lipidmetabolism modulators; phospholipase A2 (PLA2) inhibitors;apolipoprotein A1 (ApoA-1) enhancers; thyroid hormone receptor agonists;cholesterol synthesis inhibitors; and omega-3 fatty acids andderivatives thereof; substances for the treatment of obesity selectedfrom the group consisting of: sibutramine, tesofensine,tetrahydrolipstatin, cannabinoid-1 (CB-1) receptor antagonists,melanin-concentrating hormone-1 (MCH-1) antagonists, melanocortin 4(MC4) receptor agonists or partial agonists, neuropeptide Y5 (NPY5) orNPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptinmimetics, agonists of the 5HT2c receptor, combinations ofbupropione/naltrexone, combinations of bupropione/zonisamide,combinations of bupropione/phentermine, combinations ofpramlintide/metreleptin, and combinations of phentermine/topiramate;lipase inhibitors; angiogenesis inhibitors; H3 antagonists;Agouti-related protein (AgRP) inhibitors; triple monoamine uptakeinhibitors; methionine aminopeptidase type 2 (MetAP2) inhibitors; nasalformulation of the calcium channel blocker diltiazem; antisensemolecules against production of fibroblast growth factor receptor 4; andprohibitin targeting peptide-1; and drugs for influencing high bloodpressure, chronic heart failure, or atherosclerosis selected from thegroups consisting of: angiotensin II receptor antagonists,angiotensin-converting-enzyme (ACE) inhibitors,endothelin-converting-enzyme (ECE) inhibitors, diuretics, beta-blockers,calcium antagonists, centrally acting hypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, andthrombocyte aggregation inhibitors.
 26. A method for the treatment ofhyperglycemia, type 1 diabetes, type 2 diabetes, or obesity, or anycombination of these individual disease components, the methodcomprising administering to a patient in need of such treatment aneffective amount of one or more compounds, salts or solvates of claim 1.27. The method of claim 26, for the treatment of hyperglycemia, or type2 diabetes.
 28. A method for the simultaneous treatment of diabetes andobesity which comprises administering to a patient in need of suchtreatment an effective amount of one or more compounds, salts orsolvates of claim
 1. 29. A method for the treatment of hyperglycemia,type 2 diabetes, type 1 diabetes, or obesity, or any combination ofthese individual disease components, the method comprising administeringto a patient in need of such treatment an effective amount of apharmaceutical composition of claim
 24. 30. The method of claim 29, forthe treatment of hyperglycemia or type 2 diabetes.
 31. A method for thesimultaneous treatment of diabetes and obesity, the method comprisingadministering to a patient in need of such treatment an effective amountof a pharmaceutical composition of claim 24.